PURPOSE: The purpose of this study is to clarify the impact of organic anion transporting polypeptide (Oatp) on intestinal absorption of the HMG-CoA reductase inhibitor, pravastatin. METHODS: OATP/Oatp-mediated pravastatin uptake was evaluated with Xenopus oocytes systems. Intestinal permeability was measured by an in situ closed loop method in rats. In vivo pravastatin absorption was kinetically assessed by measuring plasma concentration after oral administration in rats. RESULTS: Uptake of pravastatin by Oatp1a5, Oatp2b1, OATP1A2, and OATP2B1 cRNA-injected Xenopus oocytes was significantly increased compared with that by water-injected oocytes. Naringin, a potent inhibitor of Oatps and Mdr1, decreased the Oatp1a5-mediated uptake of pravastatin with IC (50) value of 30.4 μM. Rat intestinal permeability of pravastatin was significantly reduced in the presence of 1,000 μM naringin. Similar results were obtained in in vivo absorption studies in rats. Furthermore, no significant change in the permeability was observed in the presence of elacridar, a potent inhibitor of both Mdr1 and Bcrp, though the permeability was significantly decreased in the presence of both elacridar and naringin, suggesting that Mdr1 and Bcrp are not involved in intestinal absorption of pravastatin. CONCLUSION: Oatp, but not by Mdr1 or Bcrp, contributes to the intestinal absorption of pravastatin in rats.
PURPOSE: The purpose of this study is to clarify the impact of organic anion transporting polypeptide (Oatp) on intestinal absorption of the HMG-CoA reductase inhibitor, pravastatin. METHODS:OATP/Oatp-mediated pravastatin uptake was evaluated with Xenopus oocytes systems. Intestinal permeability was measured by an in situ closed loop method in rats. In vivo pravastatin absorption was kinetically assessed by measuring plasma concentration after oral administration in rats. RESULTS: Uptake of pravastatin by Oatp1a5, Oatp2b1, OATP1A2, and OATP2B1 cRNA-injected Xenopus oocytes was significantly increased compared with that by water-injected oocytes. Naringin, a potent inhibitor of Oatps and Mdr1, decreased the Oatp1a5-mediated uptake of pravastatin with IC (50) value of 30.4 μM. Rat intestinal permeability of pravastatin was significantly reduced in the presence of 1,000 μM naringin. Similar results were obtained in in vivo absorption studies in rats. Furthermore, no significant change in the permeability was observed in the presence of elacridar, a potent inhibitor of both Mdr1 and Bcrp, though the permeability was significantly decreased in the presence of both elacridar and naringin, suggesting that Mdr1 and Bcrp are not involved in intestinal absorption of pravastatin. CONCLUSION:Oatp, but not by Mdr1 or Bcrp, contributes to the intestinal absorption of pravastatin in rats.
Authors: Wen Zhao; Jeremiah D Zitzow; Yi Weaver; David J Ehresman; Shu-Ching Chang; John L Butenhoff; Bruno Hagenbuch Journal: Toxicol Sci Date: 2017-03-01 Impact factor: 4.849
Authors: Fanfan Zhou; Jian Zheng; Ling Zhu; Andreas Jodal; Pei H Cui; Mark Wong; Howard Gurney; W Bret Church; Michael Murray Journal: AAPS J Date: 2013-08-06 Impact factor: 4.009